Xanthine compounds and method of treating bronchospastic and allergic diseases

ABSTRACT

Bronchial asthma and other bronchospastic and allergic diseases are treated by administering an effective amount of a substituted xanthine compound having the formula: ##STR1## wherein: R 1  = C 1  -C 3  alkyl, 
     R 3  = c 1  -c 7  alkyl, C 3  -C 7  alkenyl, C 3  -C 7  alkynyl, C 3  -C 7  cycloalkyl or C 4  -C 7  cycloalkylalkyl, 
     R 8  = h, c 1  -c 4  alkyl, C 3  -C 4  alkenyl, C 3  -C 4  alkynyl or C 3  -C 4  cycloalkyl, 
     R = c 1  -c 4  alkyl, 2-halo C 2  -C 3  alkyl, or phenyl 
     Novel and preferred bronchodilator and antiallergy compounds are disclosed having the formula ##STR2## wherein: R 1  = C 1  -C 2  alkyl 
     R 3  = ch 2  --(c 3  -c 4  alkyl),--CH 2  --(C 3  -C 4  alkenyl), or --CH 2  --(C 3  -C 4  cycloalkyl) 
     R 8  = h, c 1  -c 2  alkyl, 
     R = c 1  -c 4  alkyl, 2-halo C 2  -C 3  alkyl, or phenyl 
     The bronchodilator and antiallergy agents may be administered in the form of tablets, capsules or aerosols.

BACKGROUND OF THE INVENTION

This invention relates to methods for treatment of bronchial asthma and other bronchospastic and allergic diseases. More particularly it relates to a method of treating these diseases employing certain substituted xanthine compounds.

Bronchial asthma is characterized by bronchospasm caused by contraction of the bronchial smooth muscle, increased secretion of mucus from the bronchi, and edema of the respiratory mucosa. While the etiology of asthma is not completely known, it is believed to involve an allergic reaction. Allergic reactions occur in sensitized individuals who are exposed to the antigen to which they are sensitized. The antigen provokes the release in the body of certain chemicals (allergic mediators) which in turn produce the allergic symptoms. Allergic reactions can also produce effects in organs other than the bronchi, particularly the skin, eyes and nasal mucosa and include such diseases as allergic rhinitis and urticaria.

Acute asthmatic bronchospasm has been treated with drugs which relax bronchial smooth muscle. Sympathominmetic drugs such as epinephrine, isoproterenol, and terbutaline and xanthine drugs such as theophylline and its salts (aminophylline, etc.) have been used for this purpose. Drugs such as cromolyn sodium which inhibit the release of allergic mediators, have been used prophylactically to treat bronchial asthma. Corticosteriod drugs have also been used to treat bronchial asthma and other allergy diseases.

Many of the drugs used hitherto have shortcomings which make them less than ideal for treatment of asthma and other bronchospastic and allergic diseases. For example, epinephrine and isoproterenol relieve the symptoms of asthma for only a relatively short period of time and are ineffective orally. Theophylline has limited efficacy and produces cardiac and gastrointestinal side effects. Cromolyn sodium is only effective by inhalation or injection and is ineffective by oral administration. The corticosteriod drugs have serious side effects which limit their chronic use.

Substituted xanthines have been known for some time as bronchodilators, and theophylline (1,3-dimethylxanthine) has long been used in the treatment of bronchial asthma.

Prior attempts have been made to improve theophylline by substituting the xanthine nucleus with different groups in several positions in the molecule. A number of 1,3-dialkylxanthines and 1,3,8-trialkylxanthines have been shown to be bronchodilators in animal models. However, none of the substituted xanthine compounds hitherto synthesized have displaced theophylline and its salts as clinically useful bronchodilator and antiallergy agents. There are several references in the prior art disclosing the synthesis of compounds which may be considered structurally similar to the compounds of the claimed invention. However, in each case where such similarity exists, either the degree and/or duration of activity of the claimed compounds is far superior to those of the prior art or a completely different utility is disclosed in connection with the prior art compounds. Stoll (Stoll, J. H., et.al., U.S. Pat. No. 2,729,643, issued Jan. 3, 1956), for example, discloses a method for forming substituted xanthines which are said to be effective as diuretics. At one stage in the Stoll process, an intermediate compound is formed which is illustrated by Stoll in the form of a generic structural formula, although the only specific example of a compound within the context of the general formula is 1,3-diethyl-7-carboethoxyxanthine. There is no specific disclosure of a 1,3,8-trialkyl-7-carboalkoxyxanthine, nor is there any disclosure in the patent of a 3-(2-methyl-1-butyl) substituted xanthine. Certain compounds disclosed by Vieth (Vieth, H., et.al., Biochem. Z. 163, 13-26 (1925).), Cacace, (Cacace, F., et.al., Ann. Chim. (Rome) 45, 983-993 (1955).), Giani, (Giani, M., et.al., Farmaco (Pavia), Ed. Sci. 12, 1016-1024 (1957).), may also be construed as being structurally similar to the compounds of this invention, but again none of these references suggests a bronchodilating or antiallergen use. They all acknowledge the diuretic use of theophylline derivatives although Cacace and Giani have no disclosure of a utility for the 7-carboalkoxy compounds discussed therein. Armitage, (Armitage, A. K., et.al., Brit. J. Pharmacol., 17, 196-207 (1961).), and Goodsell, (Goodsell, E. G. et.al., J. Med. Chem. 1971, 14 (12) 1202-1205.), both of whom deal with di- and tri-alkyl xanthines, allege uses relating to bronchodilation, but neither reference shows a 7-carboalkoxy substituent on a xanthine nucleus and substitution in the 3-position does not include a 2-methyl-1-butyl grouping. Thus, while a similar use is involved, the compounds of this invention are hot suggested by these prior art compounds. This is especially so in light of Beavo's disclosure (Beavo, J.A., et.al., Mol. Pharmacol. 1970, 6 (6) 597-603) that in studying the adenosine 3', 5' monophosphate phosphodiesterase (PDE) inhibiting activity of substituted xanthines, which is generally conceded to be correlated with bronchodilation activity, he noted that substitution in the 7-position either has no affect or decreases the potency of the compounds tested.

A class of substituted xanthine compounds has now been found which are very effective bronchodilator and antiallergy agents with rapid onset and prolonged duration of action. These compounds are effective, rapid-acting bronchodilators by all routes of administration and accordingly can be used to abort an acute bronchospastic attack. In addition, they are orally effective, long-acting antiallergy compounds, by suppressing the release of allergic mediators. Hence, these compounds may be used prophylactically to treat bronchial asthma, and other bronchospastic and allergic diseases.

SUMMARY OF THE INVENTION

It is an object of this invention to provide a method of treating bronchial asthma and other bronchospastic and allergic diseases. A further object is to provide a method for treating bronchial asthma and other bronchospatic and allergic conditions by administering drugs comprising substituted xanthines. A further object is to provide a method of treatment which may be used prophylactically as well as in acute bronchospastic and allergic attacks. A further object is to provide a method for producing long-lasting relief of bronchial asthma and other bronchospastic and allergic diseases. A further object is to provide novel compounds for the treatment of bronchial asthma and other bronchospastic and allergic diseases. According to this invention bronchial asthma and other bronchospastic and allergic diseases are treated by administering an effective amount of a substituted xanthine compound having the formula: ##STR3## wherein: R₁ = C₁ -C₃ alkyl,

R₃ = c₁ -c₇ alkyl, C₃ -C₇ alkenyl, C₃ -C₇ alkynyl, C₃ -C₇ cycloalkyl or C₄ -C₇ cycloalkylalkyl,

R₈ = h, c₁ -c₄ alkyl, or C₃ -C₄ cycloalkyl,

R = c₁ -c₄ alkyl, 2-halo C₂ -C₃ alkyl or phenyl

These compounds may be administered orally, parenterally, or by inhalation in the form of tablets, capsules, solutions, elixirs, emulsions, aerosols and the like. Typical effective doses in man range from 0.01 to 50 milligrams per kilogram of body weight depending on route of administration and potency of compound selected. The novel compounds of this invention which are preferred as bronchodilator and antiallergy agents have the following formula: ##STR4## wherein: R₁ = C₁ -C₂ alkyl,

R₃ = ch₂ (c₃ -c₄ alkyl), --CH₂ --(C₃ -C₄ alkenyl), or --CH₂ --(C₃ -C₄ cycloalkyl),

R₈ = c₁ -c₂ alkyl

R = c₁ -c₄ alkyl, 2-halo (C₂ -C₃ alkyl), phenyl

DESCRIPTION OF PREFERRED EMBODIMENTS:

Suitable groups for R₁ in the compounds used in the method of treatment of this invention include methyl, ethyl, n-propyl and isopropyl. Suitable groups for R₃ include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, 1-methyl-1-propyl, n-pentyl, 1-methyl-1-butyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2,2-dimethyl-1-propyl, n-hexyl, 1-methyl-1-pentyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2,2-dimethyl-1-butyl, 2,3-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 1-ethyl-1-butyl, 2-ethyl-1-butyl, n-heptyl, 1-methyl-1-hexyl, 2-methyl-1-hexyl, 3-methyl-1-hexyl, 4-methyl-1-hexyl, 5-methyl-1-hexyl, 1,2-dimethyl-1-pentyl, 2,2-dimethyl-1-pentyl, 2,3-dimethyl-1-pentyl, 1,3-dimethyl-1-pentyl, 2,4-dimethyl-1-pentyl, 1-ethyl-1-pentyl, 2-ethyl-1-pentyl, 2-ethyl-3-methyl-1-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, allyl, methallyl, 2-methyl-2-buten-1-yl, 2-methyl-3-buten-1-yl, 3-methyl-2-buten-1-yl, propargyl, 2-methyl-3-butyn-1-yl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl and 2-cyclopropylethyl and the like.

Suitable groups for R₈ include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl, t-butyl, cyclopropyl and cyclobutyl.

Suitable groups for R include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-chloroethyl, 2-chloropropyl, 3-chloropropyl, 2-bromoethyl, 2-bromopropyl, 3-bromopropyl and phenyl. In this application the term "halo" signifies either chlorine or bromine.

With respect to the xanthine compounds of the prior art, the introduction of the carboalkoxy group in the 7-position of the compounds of this invention has been found to give an improvement in efficacy. For example, as shown below in Example 5, 1,3-dimethyl-7-carbomethoxyxanthine, i.e., 7-carbomethoxytheophylline or theophylline-7-carboxylic acid, methyl ester, is significantly more effective than theophylline itself. The data show that the xanthine carboxylate ester is more potent, with both faster onset and longer duration of action. These data indicate a greater bioavailability of the xanthine carboxylate ester. The 7-carboalkoxyxanthines are believed to act as latent forms of the alkylxanthine bronchodilators and are biotransformed to the corresponding xanthine-7-carboxylic acids, which then decarboxylate to yield the corresponding alkylxanthine. Thus for the case of 1,8-dimethyl-3-(2-methylbutyl)-xanthine-7-carboxylic acid, methyl ester, the major reaction sequence is thought to proceed as follows: ##STR5## It is preferred to have R₈ = methyl. The introduction of an alkyl group in the 8-position of the xanthine nucleus has been discovered to produce a compound having a long lasting activity. As shown below in Example 6, all of the 8-alkylxanthine bronchodilators have a longer duration of activity than the corresponding 8-H xanthine. It is believed that the 8-alkyl groups prevents the normal enzymic oxidation at the 8-position of xanthines and thereby prevents rapid bioinactivation of the xanthine.

It is preferred to have R₃ selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, isobutyl, n-pentyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2,2-dimethyl-1-propyl, n-hexyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-1-hexyl, methallyl, cyclopropylmethyl, cyclobutylmethyl, and 2-cyclopropylethyl groups. More preferred R₃ groups are isobutyl, 2-methyl-1-butyl, 2-methyl-1-pentyl, 3-methyl-1-butyl, n-pentyl, 2,2-dimethyl-1-propyl, methallyl, cyclopropylmethyl and cyclobutylmethyl groups. Of these the isobutyl and 2-methyl-1-butyl are most preferred and 2-methyl-1-butyl is uniquely preferred. This group has never been reported as a substituent in a xanthine compound and has a significant advantage over the prior art R₃ groups. In Comparison with the known R₃ groups, as shown below in Example 7, the 2-methyl-1-butyl group surprisingly confers on the xanthine bronchodilators an effectiveness equal to the best R₃ group reported in the prior art, the isobutyl group. This is surprising because the next higher homolog, the 2-methyl-1-pentyl group, confers much lower bronchodilation potency. Furthermore, the 2-methyl-1-butyl group surprisingly combines this great potency with a substantially lower toxicity. Thus the 2-methyl-1-butyl group is uniquely suitable for the R₃ group of a xanthine bronchodilator, particularly in combination with a 7-carboalkoxy group which, as previously indicated, increases the efficacy of the compound, and therefore such compounds which contain the 2-methyl-1-butyl group are greatly preferred.

Thus the preferred groups for R₁, R₈ and R are methyl. The most preferred group for R₃ is 2-methyl-1-butyl. The most preferred compound is that which combines all four preferred groups, namely 1,8-dimethyl-3-(2-methyl-1-butyl)-7-carbomethoxyxanthine.

The 1,3,8-trialkyl-7-carboalkoxyxanthines of this invention may be prepared by reacting the sodium salt of the corresponding 1,3,8-trialkylxanthine with an alkyl chloroformate ClCOOR According to the following reaction: ##STR6## The sodium salt of the 1,3,9-trialkylxanthine can be prepared by the action of a strong base such as sodium hydride on the 1,3,8-trialkylxanthine. The reaction can be carried out in a suitable inert solvent such as tetrahydrofuran.

The 1,3,8-trialkylxanthines can be prepared by the well-known general procedure of Traube, Berichte 33, 1371 and 3055 (1900).

A 1,3-dialkyl urea having the general formula ##STR7## is first prepared. This urea can be prepared by reacting one mole of an alkyl isocyanate with one mole of an amine according to the reaction ##STR8## It is evident from the symmetry of the product that either R₁ or R₃ may be in the isocyanate reagent and either group may be in the amine reagent. The conditions under which this well-known reaction proceeds are known to one skilled in the art.

The isocyanate required for the above reaction may be prepared by reacting the corresponding amine with phosgene according to the equation

    R.sub.1 --NH.sub.2 + COCl.sub.2 → R.sub.1 --NCO + 2 HCl

The conditions for this reaction are well known to those skilled in the art and are described in the chemical literature, e.g., in British Pat. No. 901,337.

The 1,3-dialkyl urea is next converted into a 1,3-dialkyl-1-cyanoacetylurea by reaction with cyanoacetic acid according to the following reaction: ##STR9## The reaction is conveniently carried out in acetic anhydride at 60° to 70°. The reaction gives preferentially although not exclusively the product containing the smaller alkyl group as R₁. The isomers may be separated by fractional crystallization. The 1,3-dialkyl-1-cyanoacetylurea is next cyclized to form a 4-amino-1,3-dialkyluracil according to the following reaction: ##STR10## The reaction is carried out by treating the 1,3-dialkyl-1-cyanoacetylurea with a strong base such as sodium hydroxide in an aqueous medium.

The 4-amino-1,3-dialkyl uracil is then converted into 4-amino-5-nitroso-1,3-dialkyluracil by treating with sodium nitrite in glacial acetic acid at room temperature, according to the following reaction: ##STR11## The 4-amino-5-nitroso-1,3-dialkyl-uracil is then reduced to a 4,5-diamino═1,3-dialkyluracil by reaction with sodium dithionite in ammonium hydroxide solution according to the following reaction: ##STR12## The 4,5-diamino-1,3-dialkyluracil is next converted to a 4-amino-5-alkylamino-1,3-dialkyluracil by reacting with a lower aliphatic acid according to the following equation: ##STR13## wherein R₈ is a lower group.

The 4-amino-5-alkanoylamino-1,3-dialkyluracil is then cyclized to form the 1,3,8-trialkylxanthine by heating in 10% aqueous sodium hydroxide solution to reflux temperature according to the following equation: ##STR14## The compounds of this invention wherein R₃ contains an asymmetric carbon atom can exist in optically active enantiomeric forms. These forms may exist separately or mixed in any proportions. The racemic, or equimolar mixture of enantiomeric forms is obtained in the synthesis using reagents devoid of optical activity. The optically active forms of the substituted xanthines can be prepared by using the corresponding optically active amines R₃ NH₂ in the synthesis. For example, the optically active dextro- or levo- form of the substituted xanthines having R₃ = CH₂ CH(CH₃)CH₂ CH₃ can be obtained by starting with the corresponding optically active form of 2-methylbutylamine. Dextro- and levo-2-methylbutylamines can be prepared by from the corresponding commercially available dextro- and levo-2-methylbutanols by the procedure described by Vasi, I. G., and Desai, R. K., J. Inst. Chemists Calcutta, 45, 66 (1973). ##STR15##

The compounds of this invention may be administered in the customary ways such as orally, sublingually, inhalation, rectally, and parenterally. Tablets, capsules, solutions, suspensions and aerosol mist may be used as forms for administration.

The compounds of this invention can be formulated into compressed tablets incorporating the customary inert excipients including diluents, binders, lubricants, disintegrants, colors, flavors, and sweetening agents. Commonly used pharmaceutical diluents such as calcium sulfate, lactose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar may be used.

Suitable binders for tablets include starch, gelatin, sugars, such as sucrose, glucose, lactose, molasses, natural and synthetic gums such as acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, carboxymethyl cellulose, polyvinylpyrrolidone and the like.

Commonly used lubricants which are suitable for tablets include talc, hydrogenated vegatable oils, and the like.

A suitable disintegrant may be incorporated into the tablets. Suitable disintegrants such as starches, clays, cellulose, algins, and gums may be used as is well known to those skilled in the art.

Conventional coloring agents such as pharmaceutically acceptable dyes and lakes and flavoring agents such as mannitol, lactose, or artificial sweetners may also be added to the tablet composition.

The compounds of this invention may also be administered orally contained in hard or soft capsules of gelatin or other suitable material. The compound of this invention may be present in the capsule alone or mixed with a suitable diluent such as lactose or starch.

The compounds of this invention may also be administered sublingually as rapidly disintegrating tablets or as troches or sublingual lozenges or pastilles. These dosage forms are prepared by mixing the active ingredient with flavored, rapidly dissolving or rapidly disintegrating excipients. For example a suitable base would comprise starch, lactose, sodium saccharin and talc.

Parenteral means can also be used for administering the compounds of this invention. They may be incorporated into implantable, slow-dissolving pellets or into aqueous injectable suspensions or solutions, or oily injectable media such as fixed oils. In general, the parenteral forms should be prepared just prior to use.

The compounds of this invention may also be administered by inhalation of a mist. The active compound may be dissolved or suspended in an aerosol propellant or suitable carrier liquid and loaded into a standard aerosol container with sufficient propellant to provide the proper pressure for dispensing the compound. These propellants are usually fluorinated or fluorochlorinated lower saturated alphatic hydrocarbons. The active ingredient is then dispensed through a special valve in the form of a fine mist which is inhaled.

The great potency of 1,8-dimethyl-3-(2-methyl-1-butyl)-7-carbomethoxyxanthine makes it a preferred compound for aerosol administration, like epinephrine and isoproterenol, to abort acute attacks. Aerosols of theophylline and its salts have been tried in the art, but the high doses required for these drugs to be efficacious and the resulting toxic reactions make this mode of administration impractical.

As is well-known in the pharmaceutical art, it is necessary in compounding dosage forms to avoid incompatibilities between ingredients. In formulating dosage forms containing the compounds of this invention, it is necessary to avoid combinations of ingredients which will result in the instablity of the active compound if the dosage forms are to be stored for long periods of time. The particular incompatibilities to be avoided to attain this goal will be evident to one skilled in the art for each particular dosage form. Thus, for example, aqueous dosage forms of these compounds cannot be stored for long periods of time; however, they are perfectly satisfactory dosage forms if prepared immediately before administration.

It is preferred to administer the bronchodilator and antiallergy compounds of this invention orally in the form of tablets or capsules. Preferred dosage ranges in humans are from 2 to 50 mg.

The following examples illustrate the practice of this invention but are not intended to limit its scope.

EXAMPLE 1 Synthesis of 1,8-dimethyl-3-(2-methyl-1-butyl) xanthine Step 1 ##STR16##

1.03 kg (11.8 mole) of 2-methyl-1-butylamine was added to 4.5 L of chloroform and the solution cooled to 0°-5° C.

Then 647.0 g (11.8 mole) of methyl isocyanate was added slowly while maintaining the temperature at 0.5° C.

After the addition was complete the reaction was allowed to reach room temperature. Stirring was continued for 18 hrs.

The chloroform was removed under vacuum to yield ˜ 1.7 kg of 1-methyl-3-(2-methyl-1-butyl)urea (1) - an oil. Yield 100%.

Step 2 ##STR17##

To ˜ 1.7 kg (11.8 mole) of 1-methyl-3-(2-methyl-1-butyl)-urea (1) were added 4.3 L of acetic anhydride and 1.18 kg (13.9 mole) of cyanoacetic acid. This was heated for 2 hr. σ 60°-70° C.

The acetic anhydride was removed under vacuum to yield ˜ 2.9 kg of an oil. This material is a mixture of cyano acetic acid and 1-methyl-1-cyanoacetyl-3-(2-methyl-1-butyl)urea (2) No attempt was made at purification; (2) was used immediately in the next step.

Step 3 ##STR18##

10.3 L of 10% NaOH solution was slowly added to 2.9 kg (11.8 mole) of crude 1-methyl-1-cyanoacetyl-3-(2-methyl-1-butyl) urea (2) with stirring.

The oil dissolved and shortly another oil precipitated. The temperature rose to ˜ 60° C. and then dropped.

After stirring for awhile at room temperature the oil crystallized.

After cooling the product was filtered. The crude product was slurried in water and dried at 50° C. in vacuo to yield ˜ 2.1 kg of 4-amino-1-methyl-3-(2-methyl-1-butyl) uracil (3) (m.p. 121°-124° C.). Yield 85% from (1).

Step 4 ##STR19##

21. kg (9.9 mole) of 4-amino-1-methyl-3 (2-methyl-1-butyl)-uracil (3) was suspended in 22.0 L of water. A solution of 745.5 g (10.8 mole) of sodium nitrite in 5.7 L of water was added to the suspension. Then 1.2 L of glacial acetic acid was added dropwise and the suspension was stirred for 18 hr. at room temperature.

After cooling the precipitate was filtered. The crude product was slurried in water and dried at 80° C. in vacuo to yield ˜ 1.9 kg of 4-amino-5-nitroso-1-methyl-3-(2-methyl-1-butyl)-uracil (4) (m.p. 202°-204° C.). Yield 80%.

Step 5 ##STR20##

8.65 L of conc. ammonium hydroxide (58%) was added to 1.9 kg (7.9 mole) of 4-amino-5-nitroso-1-methyl-3-(2-methyl-1-butyl)uracil (4). An orange salt formed.

The suspension was placed in an oil bath at 80°-90° C. and a solution resulted.

5.6 kg (32.3 mole) of sodium dithionite was added in portions over about 30 min. When the addition was complete stirring was continued for 30 min.

The reaction was allowed to cool to room temperature and stirred overnight.

After cooling the precipitate was filtered, slurried with water and dried at 80° C. in vacuo to yield ˜ 1.25 kg of 4,5-diamino-1-methyl-3-(2-methyl-1-butyl)uracil (5) (m.p. 161°-163° C.). Yield 70%.

Step 6 ##STR21##

1.25 kg (5.5 mole) of 4,5-diamino-1-methyl-3-(2-methyl-1-butyl) uracil (5) was added to 4.5 L of glacial acetic acid and heated to reflux for 2 hrs.

The acetic acid was evaporated and the residue triturated with ether. The solid was filtered and dried at 60° C. in vacuo to yield ˜ 1.26 kg of 4-amino-5-acetylamino-1-methyl-3-(2-methyl-1-butyl)uracil (6) (m.p. 178°-182° C.). Yield 85%.

Step 7 1,8-dimethyl-3-(2-methyl-1-butyl) xanthine (7) ##STR22##

1.26 kg (4.7 mole) of 4-amino-5-acetylamino-1-methyl-3-(2-methyl-1-butyl)uracil (6) was added to 3.9 L of 10% sodium hydroxide solution and heated at reflux for 30 min.

The solution was filtered and the filtrate cooled to room temperature.

The pH of the filtrate was adjusted to 5.0 with glacial acetic acid.

After cooling the precipitate was filtered. The crude product was slurried twice with water and dried at 80° C. in vacuo to yield about 1.0 kg of 1,8-dimethyl-3-(2-methyl-1-butyl)xanthine (7) (m.p. 189°-191° C.). Yield 85%.

EXAMPLE 2

1,3-dialkylxanthines and 1,3,8-trialkylxanthines. By the procedure of Example 1 a number of 1,3-dialkylxanthines and 1,3,8-trialkylxanthines are synthesized. By proper choice of the reagents containing the precursors of the R₁, R₃ and R₈ groups the particular compounds are synthesized. R₁ and R₃ are determined by the reagents reacted in Step 1, R₈ is determined by the carboxylic acid reagent used in Step 5. Table 1 shows the reagents used in Steps 1 and 5 to introduce R₁, R₃, and R₈, and produce the listed compound.

                                      TABLE 1                                      __________________________________________________________________________                    STEP 1               STEP 5                                     No.                                                                                Compound   isocyanate                                                                               amine       acid                                      __________________________________________________________________________     6825                                                                              1-methyl-3-ethyl-                                                                          methyl isocyanate                                                                       methylamine formic acid                                   xanthine                                                                    6826                                                                              1-methyl-3-n-propyl-                                                                       methyl isocyanate                                                                       n-propylamine                                                                              formic acid                                   xanthine                                                                    6762                                                                              1-methyl-3-isopropyl-                                                                      methyl isocyanate                                                                       isopropylamine                                                                             formic acid                                   xanthine                                                                    4315                                                                              1-methyl-3-(n-butyl)-                                                                      methyl isocyanate                                                                       n-butylamine                                                                               formic acid                                   xanthine                                                                    4258                                                                              1-methyl-3-(isobutyl)                                                                      methyl isocyanate                                                                       isobutylamine                                                                              formic acid                                   xanthine                                                                    6806                                                                              1-methyl-3-(n-pentyl)                                                                      methyl isocyanate                                                                       pentylamine formic acid                                   xanthine                                                                    4280                                                                              DL-1-methyl-3-(2-                                                                          methyl isocyanate                                                                       2-methylbutylamine                                                                         formic acid                                   methyl-1-butyl)-                                                               xanthine                                                                    4340                                                                              1-methyl-3-(2,2-                                                                           methyl isocyanate                                                                       2,2-dimethylpropyl-                                                                        formic acid                                   dimethyl-1-propyl)   amine                                                     xanthine                                                                    4372                                                                              DL-1-methyl-3-(2-                                                                          methyl isocyanate                                                                       2-methylpentylamine                                                                        formic acid                                   methyl-1-pentyl)-                                                              xanthine                                                                    4276                                                                              DL-1-methyl-3-(2-                                                                          methyl isocyanate                                                                       2-ethylhexylamine                                                                          formic acid                                   ethyl-1-hexyl)-                                                                xanthine                                                                    4306                                                                              1-methyl-3-methallyl-                                                                      methyl isocyanate                                                                       methallylamine                                                                             formic acid                                   xanthine                                                                    6788                                                                              1-methyl-3-cyclohexyl-                                                                     methyl isocyanate                                                                       cyclohexylamine                                                                            formic acid                                   xanthine                                                                    4362                                                                              1-methyl-3-cyclohexyl-                                                                     methyl isocyanate                                                                       cyclohexanemethyl-                                                                         formic acid                                   methylxanthine       amine                                                  4296                                                                              1,3,8-trimethyl-                                                                           methyl isocyanate                                                                       methylamine acetic acid                                   xanthine                                                                    6832                                                                              1,8-dimethyl-3-ethyl-                                                                      methyl isocyanate                                                                       ethylamine  acetic acid                                   xanthine                                                                    6834                                                                              1,8-dimethyl-3-n-                                                                          methyl isocyanate                                                                       n-propylamine                                                                              acetic acid                                   propylxanthine                                                              6818                                                                              1,8-dimethyl-3-                                                                            methyl isocyanate                                                                       isopropylamine                                                                             acetic acid                                   isopropylxanthine                                                           6840                                                                              1,8-dimethyl-3-                                                                            methyl isocyanate                                                                       n-butylamine                                                                               acetic acid                                   (n-butyl)-xanthine                                                          6831                                                                              1,8-dimethyl-3-                                                                            methyl isocyanate                                                                       isobutylamine                                                                              acetic acid                                   isobutylxanthine                                                            4506                                                                              1,8-dimethyl-3-n-                                                                          methyl isocyanate                                                                       pentylamine acetic acid                                   pentylxanthine                                                              4500                                                                              1,8-dimethyl-3-                                                                            methyl isocyanate                                                                       isopentylamine                                                                             acetic acid                                   isopentylxanthine                                                           6738                                                                              1,8-dimethyl-3-                                                                            methyl isocyanate                                                                       neopentylamine                                                                             acetic acid                                   (2,2-dimethylpropyl)-                                                          xanthine                                                                    6842                                                                              1,8-dimethyl-3-n-                                                                          methyl isocyanate                                                                       n-hexylamine                                                                               acetic acid                                   hexyl)xanthine                                                              4373                                                                              1,8-dimethyl-3-                                                                            methyl isocyanate                                                                       2-methyl-1-pentyl-                                                                         acetic acid                                   (2-methyl-1-pentyl)- amine                                                     xanthine                                                                    6786                                                                              1,8-dimethyl-3-(2-                                                                         methyl isocyanate                                                                       2-methyl-1-hexyl-                                                                          acetic acid                                   methyl-1-hexyl)-                                                               xanthine                                                                    6794                                                                              1,8-dimethyl-3-                                                                            methyl isocyanate                                                                       methallylamine                                                                             acetic acid                                   methylallyl-1-xanthine                                                      6787                                                                              1,8-dimethyl-3-cyclo-                                                                      methyl isocyanate                                                                       cyclohexylamine                                                                            acetic acid                                   hexylxanthine                                                               6778                                                                              1,8-dimethyl-3-cyclo-                                                                      methyl isocyanate                                                                       cyclohexanemethyl-                                                                         acetic acid                                   hexylmethylxanthine  amine                                                  6822                                                                              1,8-dimethyl-3-cyclo-                                                                      methyl isocyanate                                                                       2-cyclopropylethyl-                                                                        acetic acid                                   propylethylxanthine  amine                                                                 STEP 1               STEP 1                                     No.                                                                                Compound   isocyanate                                                                               amine       acid                                      __________________________________________________________________________     4325                                                                              1,3-dimethyl-8-ethyl-                                                                      methyl isocyanate                                                                       methylamine propionic acid                                xanthine                                                                    4328                                                                              1,3-dimethyl-8-(n-                                                                         methyl isocyanate                                                                       methylamine butyric acid                                  propyl)xanthine                                                             4331                                                                              1,3-dimethyl-8-                                                                            methyl isocyanate                                                                       methylamine isobutyric acid                               (isopropyl)xanthine                                                         4355                                                                              1,3-dimethyl-8-                                                                            methyl isocyanate                                                                       methylamine cyclopropane                                  (cyclopropyl)xanthine            carboxylic acid                            4339                                                                              1,3-dimethyl-8-                                                                            methyl isocyanate                                                                       methylamine valeric acid                                  (n-butyl)xanthine                                                           4344                                                                              1,3-dimethyl-8-                                                                            methyl isocyanate                                                                       methylamine 3-methyl-butyric                              (isobutyl)xanthine               acid                                       4345                                                                              1,3-dimethyl-8-                                                                            methyl isocyanate                                                                       methylamine 2,2-dimethyl-                                 (t-butyl)xanthine                propionic acid                             4355                                                                              1,3-dimethyl-8-                                                                            methyl isocyanate                                                                       methylamine cyclobutyl-                                   (cyclobutyl)xanthine             carboxylic acid                            6828                                                                              DL-1-methyl-3-(2-                                                                          methyl isocyanate                                                                       2-methyl-1-butyl-                                                                          3-butenoic acid                               methyl-1-butyl)-8-   amine                                                     allylxanthine                                                               6783                                                                              DL-1-methyl-3-(2-                                                                          methyl isocyanate                                                                       2-methyl-1-butyl                                                                           3-butynoic acid                               methyl-1-butyl)-8-   amine                                                     propargylxanthine                                                           6796                                                                              D-1,8-dimethyl-3-(2-                                                                       methyl isocyanate                                                                       D-2-methyl-1-butyl                                                                         acetic acid                                   methyl-1-butyl)      amine                                                     xanthine                                                                    6807                                                                              L-1,8-dimethyl-3-(2-                                                                       methyl isocyanate                                                                       L-2-methyl-1-butyl                                                                         acetic acid                                   methyl-1-butyl)      amine                                                     xanthine                                                                    4490                                                                              DL-1-methyl-3-(2-                                                                          methyl isocyanate                                                                       2-methyl-1-butyl-                                                                          propionic acid                                methyl-1-butyl)-8-   amine                                                     ethylxanthine                                                               4489                                                                              DL-1-ethyl-3-(2-                                                                           ethyl isocyanate                                                                        2-methyl-1-butyl-                                                                          acetic acid                                   methylbutyl-8-       amine                                                     methylxanthine                                                              4495                                                                              DL-1,8-diethyl-3-(2-                                                                       ethyl isocyanate                                                                        2-methyl-1-butyl-                                                                          propionic acid                                methyl-1-butyl)      amine                                                     xanthine                                                                    4388                                                                              1,8-dimethyl-3-                                                                            methyl isocyanate                                                                       isobutylamine                                                                              acetic acid                                   isobutylxanthine                                                            __________________________________________________________________________

EXAMPLE 3 ##STR23##

1.0 kg (4.0 mole) of 1,8-dimethyl-3-(2-methyl-1-butyl)-xanthine was suspended in 19.0 L of dry tetrahydrofuran.

288.0 g of sodium hydride (50% in oil) (6.0 mole) was washed with anhydrous ether and was then carefully added to the suspension.

The suspension was stirred for 1 hr (a solution resulted).

567.0 g (4.0 mole) of methyl chloroformate was slowly added.

After addition was complete the reaction was heated to reflux for 18 hrs.

Then the reaction was filtered hot. The filtrate was evaporated and the residue triturated with hexane. The resultant solid was washed with a little ether, filtered and dried at 40° C. in vacuo to yield ˜ 1.0 kg of 1,8-dimethyl-3-(2-methyl-1-butyl)xanthine-7-carboxylic acid, methyl ester (m.p. 110°-112° C.). Yield 82%.

EXAMPLE 4

1,3,8-trialkylxanthine-7-carboxylic acid esters. By the procedure of Example 3 using the corresponding 1,3,8-trialkylxanthine and ester of chloroformic acid listed in Table 2, the 1,3,8-trialkylxanthine-7-carboxylic acid esters listed in Table 2 are prepared.

                                      TABLE 2                                      __________________________________________________________________________                       REAGENTS                                                     No.                                                                                 PRODUCT       XANTHINE     CHLOROFORMIC ESTER                             __________________________________________________________________________     4260                                                                              1,3-dimethylxanthine-                                                                         1,3-dimethylxanthine                                                                         methylchloroformate                               7-carboxylic ester, methyl                                                                    (theophylline)                                                  ester                                                                       6862                                                                              1-methyl-3-ethylxanthine-                                                                     1-methyl-3-ethylxanthine                                                                     methylchloroformate                               7-carboxylic acid, methyl                                                      ester                                                                       6853                                                                              1-methyl-3-n-propylxanthine-                                                                  1-methyl-3-n-propyl-                                                                         methylchloroformate                               7-carboxylic acid, methyl                                                                     xanthine                                                        ester                                                                       6884                                                                              1-methyl-3-isopropyl-                                                                         1-methyl-3-isopropyl-                                                                        methylchloroformate                               xanthine-7-carboxylic acid,                                                                   xanthine                                                        methyl ester                                                                6896                                                                              1-methyl-3-(n-butyl)-                                                                         1-methyl-3-(n-butyl)-                                                                        methylchloroformate                               xanthine-7-carboxylic acid,                                                                   xanthine                                                        methyl ester                                                                4274                                                                              1-methyl-3-(isobutyl)                                                                         1-methyl-3-(isobutyl)-                                                                       methylchloroformate                               xanthine-7-carboxylic acid,                                                                   xanthine                                                        methyl ester                                                                6865                                                                              1-methyl-3-(n-pentyl)                                                                         1-methyl-3-(n-pentyl)-                                                                       methylchloroformate                               xanthine-7-carboxylic acid,                                                                   xanthine                                                        methyl ester                                                                4380                                                                              1-methyl-3-(2-methyl-1-                                                                       1-methyl-3-(2-methyl-                                                                        methylchloroformate                               butyl)xanthine-7-carboxylic                                                                   1-butyl)xanthine                                                acid, methyl ester                                                          6854                                                                              1-methyl-3-(2,2-dimethyl-1-                                                                   1-methyl-3-(2,2-dimethyl-                                                                    methylchloroformate                               propyl)xanthine-7-                                                                            1-propyl)xanthine                                               carboxylic acid, methyl ester                                               6857                                                                              DL-1-methyl-3-(2-methyl-1-                                                                    DL-1-methyl-3-(2-methyl-                                                                     methylchloroformate                               pentyl)xanthine-7-                                                                            1-pentyl)xanthine                                               carboxylic acid, methyl ester                                               6861                                                                              DL-1-methyl-3-(2-methyl-1-                                                                    DL-1-methyl-3-(2-methyl-                                                                     methylchloroformate                               hexyl)xanthine-7-                                                                             1-hexyl)xanthine                                                carboxylic acid, methyl ester                                               6882                                                                              1-methyl-3-methallylxanthine-                                                                 1-methyl-3-methallyl-                                                                        methylchloroformate                               7-carboxylic acid, methyl                                                                     xanthine                                                        ester                                                                       6871                                                                              1-methyl-3-cyclohexyl-                                                                        1-methyl-3-cyclohexyl-                                                                       methylchloroformate                               xanthine-7-carboxylic acid,                                                                   xanthine                                                        methyl ester                                                                6877                                                                              1-methyl-3-cyclohexyl-                                                                        1-methyl-3-cyclohexyl-                                                                       methylchloroformate                               methylxanthine-7-carboxylic                                                                   methylxanthine                                                  acid, methyl ester                                                          4378                                                                              1,3,8-trimethylxanthine-7-                                                                    1,3,8-trimethylxanthine                                                                      methylchloroformate                               carboxylic acid, methyl                                                        ester                                                                       6866                                                                              1,8-dimethyl-3-ethylxanthine-                                                                 1,8-dimethyl-3-ethyl-                                                                        methylchloroformate                               7-carboxylic acid, methyl                                                                     xanthine                                                        ester                                                                       6869                                                                              1,8-dimethyl-3-n-propyl-                                                                      1,8-dimethyl-3-n-propyl-                                                                     methylchloroformate                               xanthine-7-carboxylic acid,                                                                   xanthine                                                        methyl ester                                                                6880                                                                              1,8-dimethyl-3-isopropyl-                                                                     1,8-dimethyl-3-isopropyl-                                                                    methylchloroformate                               xanthine-7-carboxylic acid,                                                                   xanthine                                                        methyl ester                                                                6892                                                                              1,8-dimethyl-3-(n-butyl)-                                                                     1,8-dimethyl-3-(n-butyl)-                                                                    methylchloroformate                               xanthine-7-carboxylic acid,                                                                   xanthine                                                        methyl ester                                                                4507                                                                              1,8-dimethyl-3-n-pentyl-                                                                      1,8-dimethyl-3-n-pentyl-                                                                     methylchloroformate                               xanthine-7-carboxylic acid,                                                                   xanthine                                                        methyl ester                                                                4505                                                                              1,8-dimethyl-3-isopentyl-                                                                     1,8-dimethyl-3-isopentyl-                                                                    methylchloroformate                               xanthine-7-carboxylic acid,                                                                   xanthine                                                        methyl ester                                                                6897                                                                              1,8-dimethyl-3-(2,2-                                                                          1,8-dimethyl-3-(2,2-                                                                         methylchloroformate                               dimethylpropyl)xanthine-7-                                                                    dimethylpropyl)xanthine                                         carboxylic acid, methyl                                                        ester                                                                       6850                                                                              1,8-dimethyl-3-n-hexyl)-                                                                      1,8-dimethyl-3-n-hexyl)-                                                                     methylchloroformate                               xanthine-7-carboxylic acid,                                                                   xanthine                                                        methyl ester                                                                4515                                                                              DL-1,8-dimethyl-3-(2-methyl-                                                                  DL-1,8-dimethyl-3-(2-                                                                        methylchloroformate                               1-pentyl)xanthine-7-carboxylic                                                                methyl-1-pentyl)xanthine                                        acid, methyl ester                                                          4390                                                                              1,8-dimethyl-3-isobutyl-                                                                      1,8-dimethyl-3-isobutyl-                                                                     methylchloroformate                               xanthine-7-carboxylic acid,                                                                   xanthine                                                        methyl ester                                                                6888                                                                              DL-1,8-dimethyl-3-(2-methyl-                                                                  DL-1,8-dimethyl-3-(2-                                                                        methylchloroformate                               1-hexyl)xanthine-7-                                                                           methyl-1-hexyl)xanthine                                         carboxylic acid, methyl ester                                               6906                                                                              1,8-dimethyl-3-methally-                                                                      1,8-dimethyl-3-methyallyl-                                                                   methylchloroformate                               xanthine-7-carboxylic acid,                                                                   xanthine                                                        methyl ester                                                                6878                                                                              1,8-dimethyl-3-cyclohexyl-                                                                    1,8-dimethyl-3-cyclohexyl-                                                                   methylchloroformate                               xanthine-7-carboxylic acid,                                                                   xanthine                                                        methyl ester                                                                6898                                                                              1,8-dimethyl-3-cyclohexyl-                                                                    1,8-dimethyl-3-cyclohexyl-                                                                   methylchloroformate                               methylxanthine-7-carboxylic                                                                   methylxanthine                                                  acid, methyl ester                                                          6911                                                                              1,8-dimethyl-3-cyclopropyl-                                                                   1,8-dimethyl-3-cyclopropyl-                                                                  methylchloroformate                               ethylxanthine-7-carboxylic                                                                    ethylxanthine                                                   acid, methyl ester                                                          6940                                                                              1,3-dimethyl-8-ethyl-                                                                         1,3-dimethyl-8-ethyl-                                                                        methylchloroformate                               xanthine-7-carboxylic acid,                                                                   xanthine                                                        methyl ester                                                                6957                                                                              1,3-dimethyl-8-(n-propyl)-                                                                    1,3-dimethyl-8-(n-propyl)-                                                                   methylchloroformate                               xanthine-7-carboxylic acid,                                                                   xanthine                                                        methyl ester                                                                6932                                                                              1,3-dimethyl-8-(isopropyl)-                                                                   1,3-dimethyl-8-(isopropyl)-                                                                  methylchloroformate                               xanthine-7-carboxylic acid,                                                                   xanthine                                                        methyl ester                                                                6947                                                                              1,3-dimethyl-8-(cyclopropyl)-                                                                 1,3-dimethyl-8-(cyclo-                                                                       methylchloroformate                               xanthine-7-carboxylic acid,                                                                   propyl)xanthine                                                 methyl ester                                                                6922                                                                              1,3-dimethyl-8-(n-butyl)-                                                                     1,3-dimethyl-8-(n-butyl)-                                                                    methylchloroformate                               xanthine-7-carboxylic acid,                                                                   xanthine                                                        methyl ester                                                                6951                                                                              1,3-dimethyl-8-(isobutyl)-                                                                    1,3-dimethyl-8-(isobutyl)-                                                                   methylchloroformate                               xanthine-7-carboxylic acid,                                                                   xanthine                                                        methyl ester                                                                6917                                                                              1,3-dimethyl-8-(t-butyl)-                                                                     1,3-dimethyl-8-(t-butyl)-                                                                    methylchloroformate                               xanthine-7-carboxylic acid,                                                                   xanthine                                                        methyl ester                                                                6914                                                                              1,3-dimethyl-8-(cyclobutyl)-                                                                  1,3-dimethyl-8-(cyclo-                                                                       methylchloroformate                               xanthine-7-carboxylic acid,                                                                   butyl)xanthine                                                  methyl ester                                                                6928                                                                              DL-1-methyl-3-(2-methyl-1-                                                                    DL-1-methyl-3-(2-methyl-                                                                     methylchloroformate                               butyl)-8-allylxanthine-7-                                                                     1-butyl)-8-allylxanthine                                        carboxylic acid, methyl ester                                               6933                                                                              DL-1-methyl-3-(2-methyl-1-                                                                    DL-1-methyl-3-(2-methyl-                                                                     methylchloroformate                               butyl)-8-propargylxanthine-7-                                                                 1-butyl-8-propargyl-                                            carboxylic acid, methyl ester                                                                 xanthine                                                     6919                                                                              D-1,8-dimethyl-3-(2-methyl-                                                                   D-1,8-dimethyl-3-(2-                                                                         methylchloroformate                               1-butyl)xanthine-7-carboxylic                                                                 methyl-1-butyl)xanthine                                         acid, methyl ester                                                          6938                                                                              L-1,8-dimethyl-3-(2-methyl-                                                                   L-1,8-dimethyl-3-(2-                                                                         methylchloroformate                               1-butyl(xanthine-7-carboxylic                                                                 methyl-1-butyl)xanthine                                         acid, methyl ester                                                          4491                                                                              DL-1-methyl-3-(2-methyl-1-                                                                    DL-1-methyl-3-(2-methyl-                                                                     methylchloroformate                               butyl)-8-ethyl-xanthine-7-                                                                    1-butyl)-8-ethylxanthine                                        carboxylic acid, methyl ester                                               4494                                                                              DL-1-ethyl-3-(2-methyl-1-                                                                     DL-1-ethyl-3-(2-methyl-                                                                      methylchloroformate                               butyl)-8-methylxanthine-7-                                                                    butyl)-8-methylxanthine                                         carboxylic acid, methyl ester                                               4498                                                                              DL-1,8-diethyl-3-(2-methyl-                                                                   DL-1,8-diethyl-3-(2-                                                                         methylchloroformate                               1-butyl)xanthine-7-carboxylic                                                                 methyl-1-butyl)xanthine                                         acid, methyl ester                                                          4246                                                                              1,3-dimethylxanthine-7-                                                                       1,3-dimethylxanthine                                                                         ethylchloroformate                                carboxylic acid, ethyl                                                         ester                                                                       4356                                                                              1,3-dimethylxanthine-7-                                                                       1,3-dimethylxanthine                                                                         n-propyl chloroformate                            carboxylic acid, n-propyl                                                                     (theophylline)                                                  ester                                                                       4361                                                                              1,3-dimethylxanthine-7-                                                                       1,3-dimethylxanthine                                                                         isopropyl chloroformate                           carboxylic acid, ispropyl                                                                     (theophylline)                                                  ester                                                                       4275                                                                              1,3-dimethylxanthine-7-                                                                       1,3-dimethylxanthine                                                                         n-butyl chloroformate                             carboxylic acid, n-butyl                                                                      (theophylline)                                                  ester                                                                       4273                                                                              1,3-dimethylxanthine-7-                                                                       1,3-dimethylxanthine                                                                         isobutyl chloroformate                            carboxylic acid, isobutyl                                                                     (theophylline)                                                  ester                                                                       4477                                                                              DL-1,8-dimethyl-3-(2-methyl-                                                                  DL-1,8-dimethyl-3-(2-                                                                        ethyl chloroformate                               1-butyl)xanthine-7-carboxylic                                                                 methyl-1-butyl)                                                 acid, ethyl ester                                                                             xanthine                                                     4488                                                                              DL-1,8-dimethyl-3-(2-methyl-                                                                  DL-1,8-dimethyl-3-(2-                                                                        n-propyl chloroformate                            1-butyl)xanthine-7-carboxylic                                                                 methyl-1-butyl)xanthine                                         acid, n-propyl ester                                                        4278                                                                              1,3-dimethylxanthine-7-                                                                       1,3-dimethylxanthine                                                                         2-chloroethylchloro-                              carboxylic acid, 2-          formate                                           chloroethyl ester                                                           4262                                                                              1,3-dimethylxanthine-7-                                                                       1,3-dimethylxanthine                                                                         phenylchloroformate                               carboxylic acid, phenyl                                                        ester                                                                       6852                                                                              DL-1,8-dimethyl-3-(2-                                                                         DL-1,8-dimethyl-3-(2-                                                                        2-chloroethyl-                                    methyl-1-butyl)xanthine-                                                                      methyl-1-butyl)xanthine                                                                      chloroformate                                     7-carboxylic acid, 2-                                                          chloroethyl ester                                                           6860                                                                              DL-1,8-dimethyl-3-(2-                                                                         DL-1,8-dimethyl-3-(2-                                                                        phenylchloroformate                               methyl-1-butyl)xanthine-                                                                      methyl-1-butyl)xanthine                                         7-carboxylic acid, phenyl                                                      ester                                                                       __________________________________________________________________________

In the following comparative examples results of pharmacological tests with a number of the compounds of this invention and of the prior art are presented. The pharmacological properties were evaluated by standard tests which are defined, together with the symbols used as follows:

BD Bronchodilator activity evaluated against histamine-induced bronchoconstriction in the guinea pig, and expressed as % protection at the stated time interval (in minutes and hours) post-drug against histamine agonist. Doses are expressed in milligrams per kilogram of body weight (mpk) per os (po) or intraperitoneally (ip).

A modification of the method of Siegmund. O.H., et al., J. Pharmacol. and Exp. Therap. 90:254-9, 1947, is used. Healthy guinea pigs weighing from 250 to 300 grams are placed four at a time and separated by wiring screening in an 11 liter plastic chamber, at the time of peak activity following drug administration. The challenge consists of histamine diphosphate (1% solution) aerosolized in a de Vilbiss -40 nebulizer at 200 mm Hg. Times for prostration are recorded. All animals exposed to the aerosols for 10 minutes or longer without prostration, are arbitrarily considered fully protected.

Per cent protection is calculated as follows: ##EQU1## wherein the times are measured in seconds.

CP Cardiopulmonary activity evaluated against histamine-induced bronchoconstriction in the dog and expressed as % increase (↑) or decrease (↓) in the following parameters:

Bp blood pressure

Hr heart rate

Pr pulmonary resistance

Pc pulmonary compliance

Rmv respiratory minute volume

The method used is that of Giles, R. E., Finkel, N. P., and Mazurowski, J., Arch. Int. Pharmacodyn. Therap. 194, 213 (1971). A simulated asthmatic state is induced in anesthetized spontaneously breathing dogs by graded intravenous doses of histamine. The degree of induced bronchoconstriction is reflected by proportionate increases in pulmonary resistance. Pretreatment with bronchodilator drugs aims to block the bronchospastic response to histamine. Each dog serves as its own control. Mean values 2 hours post drug are given.

SP Spasmolytic activity evaluated in vitro using guinea pig tracheal chain preparation, and expressed as the molar (M) concentration required to produce maximum relaxation.

The method used in that of Castillo and de Beer, J. Pharmac. Expt. Therap. 90, 104, 1947.

AA Antiallergy (anti-anaphylactic) activity evaluated against antigen-induced bronchconstriction in rats sensitized with N. brasliensis, and expressed as % protection (R).

The method used in that of Church, N. K., Collier, H. O. J., and James, G. W. L., Brit. J. Pharmacol. 46, 56-65 (1972). Rats sensitized with antigen from Nippostrongylus brasiliensis exhibit anaphylactic shock when re-exposed to this antigen 28 days later. The animals are subdivided into control and test groups. Test animals receive a drug either orally, intraperitoneally or intravenously and are challenged with intravenous antigen at fixed time intervals after dosing. Antigen-induced increases in tracheal pressure are monitored and reflect the extent of bronchoconstriction.

PCA Antianaphylactic activity against passive cutaneous anaphylaxis in the rat, expressed as % protection against antigen-induced wheal formation.

The method used is that of Ogilvie, B. M., Immunology 12, 113-131 (1967). Reaginic AgE antibodies develope in the rat following subcutaneous injection of Nippostrongylus brasiliensis larvae. Antisera, collected 28 days later are injected subcutaneously into new rats. These new rats when challenged with antigen 24 hours later exhibit an immediate type I reaction characterized by local swelling and edema (wheal) at the site of antisera injection.

LD₅₀ Dose required to cause death of 50% of test animals.

The LD₅₀ was determined in three species, the mouse (male, 18-25 g), the albino rat (female, 150-200 g) and the albino guinea pig (male 180-280 g) by oral administration and in the albino rat by intraperitoneal administration. The animals are fasted overnight prior to testing. Six groups of ten animals are used; five groups are dosed with the test substance, the sixth group serves as a control and receives the drug vehicle at the highest test concentration. The compounds were administered in a 0.5% gum tragacanth solution in distilled water using a constant logarithmic increment in dose. Dose volume ranged from 5 to 40 mg/kg.

The animals were housed five per cage (rat and guinea pig) or ten per cage (mouse) with free access to food and water. The number of dead animals was recorded daily for five consecutive days. The total mortality per group of ten for each dose level was recorded and and LD₅₀ with Confidence Limits calculated according to the method described by Weil, C. S., Biometrics 8(3): 249-263, 1952.

EXAMPLE 5

This example illustrates the superiority of 7-carboalkoxyxanthines over the corresponding 7-H xanthines. Several pairs of compounds were tested in a number of assays as described above.

The results may be seen in Table 4 wherein corresponding xanthines with and without the 7-carbomethoxy group are compared. The effect can be seen most clearly by comparing the potency of the compounds in the bronchodilation assay in the guinea pig (BD[guinea pig]).

In interpreting the BD data it should be noted that a dose giving less than 40-50% protection is not considered useful. Differences in percent protection of less than 10% are probably not significant. 4378 gives 96% protection at 1 hour at a dose of 60 mpK while the corresponding compound devoid of the 7-carbomethoxy groups, 4296, gives only 53% protection at the larger dose of 100 mpK. Clearly, the 7-carbomethoxy derivative is superior. 4274 gives greater protection than 4258 at equal doses. In comparing 4387 and 4383 at equal doses (10 mpK) it can be seen that the 7-carbomethoxy compound 4387 shows greater activity. Although both of these compounds are already very potent, the benefit of the 7-carbomethoxy group is particularly evident in the dog at 1 mpK. Another comparison shows that 4260 is clearly superior to theophylline at the same dose (80 mpK).

                                      TABLE 3                                      __________________________________________________________________________     EFFECT OF 7-CARBOMETHOXY GROUP ON POTENCY                                       ##STR24##                                                                                                                     SP                                                        BD (guinea pig)                                                                            AA   (rat)                                                                             in vitro                                                                             LD.sub.50                 CPD. R.sub.1                                                                           R.sub.3                                                                                R.sub.8                                                                          R.sub.7                                                                               mpK 30'  1h 2h 4h 6h 10h                                                                     mpK  1h  C    mpK  spec                 __________________________________________________________________________     4296 CH.sub.3                                                                          CH.sub.3                                                                              CH.sub.3                                                                          H      100po53   45 43 23                                                             150po 68  80 71 79 86 85                                                                     75ip 49 M/14                            4378 CH.sub.3                                                                          CH.sub.3                                                                              CH.sub.3                                                                          COOCH.sub.3                                                                            60po96   95 89                                                                              75ip 54 M/10                            4258 CH.sub.3                                                                          CH.sub.2 CHMe.sub.2                                                                   H  H       15po 45  75  1.5ip                                                                               79 M/1000                                                    25po lethal 2/4                                                                             2.0ip                                                                               tox                                4274 CH.sub.3                                                                          CH.sub.2 CHMe.sub.2                                                                   H  COOCH.sub.3                                                                            15po 92  87 64 18                                                                           5ip  74 M/2000                                                    40po lethal 1/6                                      4383 CH.sub.3                                                                          CH.sub.2 CHMeEt                                                                       CH.sub.3                                                                          H       10po 35  6366                                                                               2.5po                                                                               58 M/1000                                                                               21.7po                                                                              g. pig                                         20po92  100 97             24.6ip                                                                              rat                                                                 88.7po                                                                               887.po                                                                              rat                                                                       60.6po                                                                              mouse                4387 CH.sub.3                                                                          CH.sub.2 CHMeEt                                                                       CH.sub.3                                                                          COOCH.sub.3                                                                            10po 44  8759 37     M/1000                                                                               27.4po                                                                              g. pig                                         20po9492     2.5po                                                                               72       54.9po                                                                              mouse                                                       5po  68                                                                        10po 57                                                                        5ip  55       18.3ip                                                                              rat                                                                       60.0po                                                                              rat                                                         75ip 70                                 Theo-                                                                               CH.sub.3                                                                          CH.sub.3                                                                              H  H       80po 32  69 42 17                                                                           25po 50 M/10   183po                                                                              g. pig               phylline                 100po 45  58 36 25 14                                                                        100po                                                                               73        225po                                                                              rat                                                                        150ip                                                                              rat                  4260 CH.sub.3                                                                          CH.sub.3                                                                              H  COOCH.sub.3                                                                            80po 99 100 86 95 0                                                                         75ip 82 M/20                            __________________________________________________________________________

example 6

this example illustrates the prolonged activity of the 8-alkylxanthines over that of the corresponding 8-H compounds. The increased & prolonged activity of the 1,3,8-trialkyl-7-carboalkoxyxanthines relative to that of the 1,3-dialkyl-7-carboalkoxyxanthines may be seen in Table 4 which compares the activity of corresponding pairs of substituted xanthines with and without 8-alkyl groups.

The data on bronchodilator activity in the guinea pig (BD[guinea pig]) show the prolonged activity of the compounds having an 8-alkyl group. In each pair the protection at 4 hours or 6 hours produced by the 8-methyl compound is greater than the protection by the corresponding compound devoid of the 8-methyl group. For pairs 4387 vs. 4380, 4390 vs. 4274, and 4378 vs. 4260, the 8-methyl derivatives are shown to be effective at lower doses and for longer duration that the 8-H compounds. This phenomenon is attributed to the 8-alkyl substitutent interfering with the normal bioinactivation of 1,3-dialkylxanthines by enzymatic oxidation at the 8-position, and was not anticipated by the teachings of the prior art on xanthine compounds.

                                      TABLE 4                                      __________________________________________________________________________     PROLONGED ACTIVITY OF 8-ALKYLXANTHINES                                          ##STR25##                                                                                                                     SP                                                        BD (guinea pig)                                                                            AA (rat)                                                                               in vitro                                                                             LD.sub.50                 CPD. R.sub.1                                                                           R.sub.3                                                                               R.sub.8                                                                           R.sub.7                                                                               mpK 30'  1h 2h 4h 6h 10h                                                                     mpK  1h  C    mpK  spec                 __________________________________________________________________________     4274 CH.sub.3                                                                          CH.sub.2 CHMe.sub.2                                                                   H  COOCH.sub.3                                                                           15po  92 87 64 18                                                                            5ip  74 M/2000                                                   40po  lethal 1/6                                      4390 CH.sub.3                                                                          CH.sub.2 CHMe.sub.2                                                                   CH.sub.3                                                                          COOCH.sub.3          2ip  60 M/1000                                                                               25.2po                                                                              g. pig                                        10po  49 86   79 48                                                                          4ip  52       27.6po                                                                              mouse                                                       2.5po                                                                               77        9.1ip                                                                              rat                                                                       33.5po                                                                              rat                  4260 CH.sub.3                                                                          CH.sub.3                                                                              H  COOCH.sub.3                                                                           80po  99 100 86 95  0                                                                        75ip 82 M/20                            4378 CH.sub.3                                                                          CH.sub.3                                                                              CH.sub.3                                                                          COOCH.sub.3                                                                           60po  96  95 89                                                                              75ip 54 M/10                            4380 CH.sub.3                                                                          CH.sub.2 CHMeEt                                                                       H  COOCH.sub.3                                                                           40po  99  57 12                                                                              5po  66 M/700                                                    20po  64                                              4387 CH.sub.3                                                                          CH.sub.2 CHMeEt                                                                       CH.sub.3                                                                          COOCH.sub.3                                                                           10po  44 87   59 37   M/1000                                                                               27.4po                                                                              g. pig                                        20po  94   92 2.5po                                                                               72       54.9po                                                                              mouse                                                       5po  68                                                                        10po 57       18.3ip                                                                              rat                                                                       60.0po                                                                              rat                  __________________________________________________________________________

EXAMPLE 7

This example illustrates the decreased toxicity of substituted xanthines having R₃ = 2-methyl-1-butyl over those having R₃ = isobutyl while the potency of the compounds remains approximately equal.

The unexpected improvement in activity of 1-alkyl-3-(2-methyl-1-butyl)-7-carbomethoxy xanthines, without a corresponding increase in toxicity with reference to the corresponding 3-isobutyl homologs can be seen in Table 5 where the data for corresponding pairs of compounds is presented. This effect is seen most clearly in the pair 4387 vs. 4390. The effectiveness of the 7-carbomethoxy compounds can be compared in the bronchodilation assay in the guinea pig and in the antiallergy assay in the rat. The effectiveness data show that the 1-methyl-3-(2-methyl-1-butyl)-8-methyl-7-carbomethoxyxanthines (4387) is about as effective as the corresponding 3-isobutyl compound (4390) in the guinea pig, rat and dog assays. Yet 4387 is only about one-half as lethal as 4390 in the rat and mouse. Likewise, in the guinea pig toxic effects can be seen in the case of the xanthines having the 3-isobutyl group, while at the same dose the corresponding compound having the 3-(2-methyl-1-butyl) group is effective and non-toxic.

                                      TABLE 5                                      __________________________________________________________________________     EQUAL ACTIVITY WITHOUT INCREASED TOXICITY                                      3-(2-METHYLBUTYL) VS. 3-ISOBUTYL                                                ##STR26##                                                                                                                 AA    SP                                                 BD (guinea pig)       (rat) in vitro                                                                            LD.sub.50               Cpd.                                                                              R.sub.1                                                                           R.sub.3                                                                               R.sub.8                                                                           R.sub.7                                                                              mpK 30'                                                                               1h 2h 4h 6h 10h                                                                               mpK 1h                                                                               C    mpK spec.               __________________________________________________________________________     4390                                                                              CH.sub.3                                                                          CH.sub.2 CHMe.sub.2                                                                   CH.sub.3                                                                          COOCH.sub.3                 2ip 60                                                                               M/1000                                                                              25.2po                                                                             g. pig                                    10po                                                                               49 86       79 48 4ip 52     27.6po                                                                             mouse                                     20po                                                                               lethal 1/2                   9.1ip                                                                              rat                                                             2.5po                                                                              77     33.5po                                                                             rat                 4387                                                                              CH.sub.3                                                                          CH.sub.2 CHMeEt                                                                       CH.sub.3                                                                          COOCH.sub.3                                                                          10po                                                                               44 87       59 37       M/1000                                                                              27.4po                                                                             g. pig                                    20po   94       92    2.5po                                                                              72     54.9po                                                                             mouse                                                           5po 68                                                                         10po                                                                               57                                                                         5ip 55     18.3ip                                                                             rat                                                                        60.0po                                                                             rat                 4274                                                                              CH.sub.3                                                                          CH.sub.2 CHMe.sub.2                                                                   H  COOCH.sub.3                                                                          15po                                                                               92 87 64 18       5ip 74                                                                               M/2000                                             40po                                                                               lethal 1/6                                           4380                                                                              CH.sub.3                                                                          CH.sub.3 CHMeEt                                                                       H  COOCH.sub.3                                                                          40po   99    57 12    5po 66                                                                               M/700                                              20po   64                                                __________________________________________________________________________

EXAMPLE 8

This example illustrates the activity of substituted xanthines according to this invention and the variation in pharmacological effects produced by introducing different R₃ substituents.

Table 6 shows the results of the bronchodilation assay described above in the guinea pig for a series of 1,3-dialkyl and 1,3,8-trialkylxanthine-7-carboxylates in which the R₃ group was varied. The most effective compounds are those in which the lowest dose produces an acceptable bronchodilation (˜40%). Data is also included showing effectiveness in the antiallergy assay in the rat, and the in vitro bronchodilation activity.

The data for the effectiveness of the compounds shown in the Table 6 teaches that the activity of xanthine bronchodilators depends not only upon the total number of carbon atoms comprising R₁, R₃, R₈ and R, but also upon the distribution of these carbon atoms among R₁, R₃, R₈ and R, and especially upon the branching within the structure of the R₃ group.

Maximum activity is obtained when R₁ ═R₈ ═R═methyl and R₃ is a C₄ or C₅ alkyl group. Peak activity is obtained when the alkyl group of R₃ is branched at the number 2 carbon ##STR27## as in 2-methyl-1-butyl. Optimal activity, i.e., maximum activity with relatively lowest toxicity is obtained when R₃ is a 2-methyl-1-butyl group. Of all the possible C₄ and C₅ alkyl groups, only the 2-methyl-1-butyl group is both primary and asymmetric, i.e., capable of existing as dextro and levo forms.

                                      TABLE 6                                      __________________________________________________________________________     BRONCHODILATION ACTIVITY OF 1,3,8-TRIALKYL-7-                                  CARBOMETHOXYXANTHINES                                                                                                                   SP                                               BD (guinea pig)       AA (rat)                                                                               in vitro              CK R   R.sub.3 R.sub.8                                                                            R.sub.7 mpK 30'                                                                               1h 2h                                                                               4h                                                                               6h                                                                               8h                                                                               10h mpK  1h C                     __________________________________________________________________________     4274                                                                              CH.sub.3                                                                           CH.sub.2 CHME.sub.2                                                                    H   COOCH.sub.3                                                                            15po                                                                               92 87 64                                                                               18        5ip  74 M/2000                                           40po                                                                               lethal 1/6                                      4380                                                                              CH.sub.3                                                                           CH.sub.2 CHMeEt                                                                        H   COOCH.sub.3                                                                            40po   99   57                                                                               12      5po   66                                                                               M/700                                                   64                                           4377                                                                              CH.sub.3                                                                           CH.sub.2 CHMePr                                                                        H   COOCH.sub.3                                                                            80po   72   0                                                                  20po   64                                           4378                                                                              CH.sub.3                                                                           CH.sub.3                                                                               CH.sub.3                                                                           COOCH.sub.3                                                                            60po   96   95                                                                               89      75ip 54 M/10                  4390                                                                              CH.sub.3                                                                           CH.sub.2 CHMe.sub.2                                                                    CH.sub.3                                                                           COOCH.sub.3                   2ip  60 M/1000                                           10po                                                                               49 86     79  48  4ip  52                                                                        2.5po                                                                               77                       4387                                                                              CH.sub.3                                                                           CH.sub.2 CHMeEt                                                                        CH.sub.3                                                                           COOCH.sub.3                                                                            10po                                                                               44 87     59  37          M/1000                                           20po   94     92      2.5po                                                                               72                                                                        5po  68                                                                        10po 57                                                                        5ip  55                       4477                                                                              CH.sub.3                                                                           CH.sub.2 CHMeEt                                                                        CH.sub.3                                                                           COOC.sub.2 H.sub.5                                                                     10po                                                                               47 87     50                                    4488                                                                              CH.sub.3                                                                           CH.sub.2 CHMeEt                                                                        CH.sub.3                                                                           COOC.sub.3 H.sub.7 (n)                                                                 10po   24     44                                                               20po   78     68                                                               40po   100    89                                                               80po                                                                               lethal 1/4                                      4491                                                                              CH.sub.3                                                                            ##STR28##                                                                             C.sub.2 H.sub.5                                                                    COOCH.sub.3                                                                            10po 40po                                                                             25 52  21                                    4494                                                                              C.sub.2 H.sub.5                                                                     ##STR29##                                                                             CH.sub.3                                                                           COOCH.sub.3                                                                            10po 40po                                                                             0 9    49 80                                                            80po                                                                               lethal 2/2                                      4498                                                                              C.sub.2 H.sub.5                                                                     ##STR30##                                                                             C.sub.2 H.sub.5                                                                    COOCH.sub.3                                                                            40po 80po                                                                             15 63  38 79                                 4507                                                                              CH.sub.3                                                                           CH.sub.2 (CH.sub.2).sub.3 Me                                                           CH.sub.3                                                                           COOCH.sub.3                                                                            10po   26     --                                                               20po   52     --                                                               40po   100    63                                                               80po                                                                               lethal 2/2                                      4505                                                                              CH.sub.3                                                                            ##STR31##                                                                             CH.sub.3                                                                           COOCH.sub.3                                                                            10po 40po                                                                              --    15 --                                                            80po                                                                               lethal 3/5                                      4515                                                                              CH.sub.3                                                                            ##STR32##                                                                             CH.sub.3                                                                           COOCH.sub.3                                                                            20po 40po                                                                             7 100  -- --                                 __________________________________________________________________________

EXAMPLE 9

This example illustrates the antiallergy properties of the compounds of this invention.

1,8-Dimethyl-3-(2-methyl-1-butyl)-7-carbomethoxyxanthine and 1,8-dimethyl-3-isobutyl-7-carbomethoxyxanthine were tested in the rat passive cutaneous anaphylaxis screen described above. The data in Table 7 shows that these compounds are effective antiallergy agents.

                                      TABLE 7                                      __________________________________________________________________________     PERCENT PROTECTION IN THE RAT PASSIVE CUTANEOUS ANAPHYLAXIS SCREEN                                Dose Wheal Diameter (cm): Mean ± S.E.M.                                     (mg/kg)                                                                             Wheal Intensity: Mean ± S.E.M.                      No.                     -                                                         Compound        & Route                                                                             Control                                                                              Response                                                                             % Δ                                                                         Control                                                                              Response                                                                             % Δ                   __________________________________________________________________________     4387                                                                              1,8-dimethyl-3-(2-methyl-1-butyl)-                                                             10po 2.39 ± 0.10                                                                       1.41 ± 0.17                                                                       41 2.46 ± 0.13                                                                       1.65 ± 0.20                                                                       33                             7-carbomethoxyxanthine                                                                         20po 1.90 ± 0.15                                                                       0.81 ± 0.13                                                                       57 1.91 ± 0.21                                                                       1.18 ± 0.21                                                                       38                          4380                                                                              1,8-dimethyl-3-isobutyl-7-                                                                     20po 1.86 ± 0.15                                                                       0.74 ± 0.21                                                                       60 2.35 ± 0.21                                                                       1.10 ± 0.23                                                                       53                             carbomethoxyxanthine                                                        __________________________________________________________________________

EXAMPLE 10

This example illustrates the effectiveness of the compounds of this invention in the dog.

The results of studies of cardiopulmonary activity in the dog by the above described procedures are shown in Table 8. The data show that compounds 4390 and 4387 significantly reduce the decrease in pulmonary compliance and increase in pulmonary resistance due to histamine administration. The corresponding values for theophylline, a clinically used xanthine bronchodilator, are shown for comparison. It can be seen that the compounds of this invention are more potent bronchodilators than theophylline in the dog.

                  TABLE 8                                                          ______________________________________                                         CARDIOPULMONARY ACTIVITY IN THE DOG                                                   CP (dog) (mean value at 2h)                                                    mpK   BP      HR      PC    PR    RMV                                   ______________________________________                                         4387     1po     ↓17                                                                             ↑40                                                                            ↑40                                                                            ↓61                                                                           ↑39                                    2po     ↓03                                                                             ↑16                                                                            ↑60                                                                            ↓85                                                                           ↑10                                    3po     ↓08                                                                             ↑08                                                                            ↑74                                                                            ↓100                                                                          ↑68                                    4po     ↓25                                                                             ↑17                                                                            ↑42                                                                            ↓77                                                                           ↑76                           4390     3po     ↓07                                                                             ↑13                                                                            ↑70                                                                            ↓85                                                                           ↑41                           Theophylline                                                                            40po    ↓08                                                                             ↑06                                                                            ↑25                                                                            ↓36                                                                           ↑38                           ______________________________________                                    

EXAMPLE 11 Tablets

19.5 grams of starch are dried to a moisture content of 10%. 0.5 grams of 1,8-dimethyl-3-(2-methyl-1-butyl)-7-carbomethoxyxanthine in finely powdered form are thoroughly mixed with the starch. The mixture is compressed into slugs. The slugs are reground into powder of 14-16 mesh size. This powder is recompressed into tablets weighing 200 mg. each. Each tablet thus has the composition:

1,8-dimethyl-3-(2-methyl-1-butyl)-7-carbomethoxyxanthine; 5 mg

Starch; 195 mg

EXAMPLE 12 Capsules

A dry mixuture os 19.5 grams of starch and 0.5 grams of 1,8-dimethyl-3-(2-methyl-1-butyl)-7-carbomethoxyxanthine is prepared as described in Example 10. The powder is loaded into hard gelatin capsules so that each capsule contains 200 mg of the powder.

EXAMPLE 13 Sublingual Tablets

Tablets for sublingual administration were prepared by standard procedure, each tablet containing 5 mg of 1,8-dimethyl-3-(2-methyl-1-butyl)-7-carbomethoxyxanthine in a rapidly disintegrating base comprising starch, lactose, sodium saccharin and talcum.

EXAMPLE 14 Aerosol

Five grams of 1,8-dimethyl-3-(2-methyl-1-butyl)-7-carbomethoxyxanthine were dissolved in 1000 grams of a mixture of 20 parts by weight of dichlorodifluoromethane and 80 parts by weight of 1,2-dichloro-1,1,2,2-tetrafluoroethane and loaded into a conventional aerosol medication dispenser to provide a means of administering the active ingredient by inhalation. 

I claim:
 1. A compound having the formula: ##STR33## wherein R₁ = C₁ -C₂ alkylR₈ = h, c₁ -c₄ alkyl R = c₁ -c₄ alkyl, 2-halo-(C₂ -C₃ alkyl), or phenyl
 2. A compound according to claim 1 wherein R₈ is ethyl.
 3. A compound according to claim 1 wherein R₈ is methyl.
 4. A compound according to claim 1 wherein R is ethyl.
 5. A compound according to claim 1 wherein R is methyl.
 6. 1,8-dimethyl-3-(2-methyl-1-butyl)-7-carbomethoxyxanthine.
 7. dextro-1,8-dimethyl-3-(2-methyl-1-butyl)-7-carbomethoxyxanthine.
 8. levo-1,8-dimethyl-3-(2-methyl-1-butyl)-7-carbomethoxyxanthine.
 9. 1,8-dimethyl-3-(2-methyl-1-butyl)-7-carboethoxyxanthine.
 10. dextro-1,8-dimethyl-3-(2-methyl-1-butyl)-7-carboethoxyxanthine.
 11. levo-1,8-dimethyl-3-(2-methyl-1-butyl)-7-carboethoxyxanthine.
 12. 1,8-dimethyl-3-(2-methyl-1-butyl)-7-carbopropoxyxanthine.
 13. 1-methyl-3-(2-methyl-1-butyl)-7-carbomethoxyxanthine.
 14. dextro-1-methyl-3-(2-methyl-1-butyl)-7-carbomethoxyxanthine.
 15. levo-1-methyl-3-(2-methyl-1-butyl)-7-carbomethoxyxanthine.
 16. A pharmaceutical composition comprising an amount effective for bronchodilation of a compound of the formula: ##STR34## wherein R₁ = C₁ -C₂ alkylR₃ = ch₂ --(c₃ -c₄ alkyl), CH₂ --(C₃ -C₄ alkenyl), CH₂ --(C₃ -C₄ --cyclo--alkyl) R₈ = h, c₁ -c₄ alkyl R = c₁ -c₄ alkyl, 2-halo--(C₂ -C₃ alkyl), or phenylin combination with a non-toxic inert pharmaceutically acceptable diluent to give a dosage form selected from tablets, capsules, or aerosol mists.
 17. A composition according to claim 16 in the form of a tablet.
 18. A composition according to claim 16 in the form of a capsule.
 19. A composition according to claim 16 in the form of a sublingual tablet.
 20. A composition according to claim 16 wherein said diluent is an aerosol propellant.
 21. A composition according to claim 16 comprising 1,8-dimethyl-3-(2-methyl-1-butyl)-7-carbomethoxyxanthine dissolved in a pharmaceutically acceptable aerosol propellant.
 22. A pharmaceutical composition in the form of a tablet comprising between 2 mg and 50 mg of a compound according to claim 16 in combination with non-toxic pharmaceutically acceptable excipients.
 23. The method of producing bronchodilation and suppressing the release of allergic mediators in mammals by administering to a mammal in need thereof an effective amount of a substituted xanthine having the formula: ##STR35## wherein R₁ = C₁ -C₃ alkyl,R₃ = c₁ -c₇ alkyl, C₃ -C₇ alkenyl, C₃ -C₇ alkynyl, C₃ -C₆ cycloalkyl or C₄ -C₇ cycloalkylalkyl, R₈ = h, c₁ -c₄ alkyl, C₃ -C₄ alkenyl, C₃ -C₄ alkynyl, or C₃ -C₄ cycloalkylalkyl R = c₁ -c₄ alkyl, 2-halo C₂ -C₃ alkyl, or phenyl
 24. A method according to claim 23 wherein R₁ is methyl.
 25. A method according to claim 23 wherein R₃ is --CH₂ (C₁ -C₆ alkyl).
 26. A method according to claim 23 wherein R₃ is --CH₂ --(C₃ -C₆ cycloalkyl).
 27. A method according to claim 23 wherein R₃ is selected from the group consisting of methyl, ethyl, n-propyl, methallyl, n-butyl, isobutyl, n-pentyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2,2-dimethylpropyl, 2-methyl-1-pentyl, cyclopropylmethyl, and cyclobutylmethyl.
 28. A method according to claim 23 wherein R₃ is 2-methyl-1-butyl.
 29. A method according to claim 23 wherein R₃ is isobutyl.
 30. A method according to claim 23 wherein R₈ is C₁ -C₄ alkyl.
 31. A method according to claim 30 wherein R₈ is methyl.
 32. A method according to claim 23 wherein R is C₁ -C₄ alkyl.
 33. A method according to claim 32 wherein R is methyl.
 34. A method according to claim 32 wherein R is ethyl.
 35. A method according to claim 23 wherein said substituted xanthine is dl-1,8-dimethyl-3-(2-methyl-1-butyl)-7-carbomethoxyxanthine.
 36. A method according to claim 23 wherein said substituted xanthine is dextro-1,8-dimethyl-3-(2-methyl-1-butyl)-7-carbomethoxyxanthine.
 37. A method according to claim 23 wherein said substituted xanthine is levo-1,8-dimethyl-3-(2-methyl-1-butyl)-7-carbomethoxyxanthine.
 38. A method according to claim 23 wherein said substituted xanthine is 1,8-dimethyl-3-(2-methyl-1-butyl)-7-carboethoxyxanthine.
 39. A method according to claim 23 wherein said substituted xanthine is 1,8-dimethyl-3-(2-methyl-1-butyl)-7-carbopropoxyxanthine.
 40. A method according to claim 23 wherein said substituted xanthine is 1,8-dimethyl-3-isobutyl-7-carbomethoxyxanthine.
 41. A method according to claim 23 wherein said substituted xanthine is 1,8-dimethyl-3-isobutyl-7-carboethoxyxanthine.
 42. A method according to claim 23 wherein said substituted xanthine is administered to humans in a dose of between 0.2 and 200 mg.
 43. A method according to claim 23 wherein said substituted xanthine is incorporated with inert excipients into a capsule and administered orally.
 44. A method according to claim 23 wherein said substituted xanthine is incorporated with inert excipients into a tablet and administered orally.
 45. A method according to claim 23 wherein said substituted xanthine is incorporated with inert excipients into a rapidly disintegrating tablet and administered sublingually.
 46. A method according to claim 23 wherein said substituted xanthine is incorporated with propellant and solvent into an aerosol and administered by inhalation of the mist.
 47. A method according to claim 23 wherein said substituted xanthine is incorporated with fatty vehicles into a suppository and administered rectally.
 48. A method according to claim 23 wherein said substituted xanthine is incorporated with a sterilized vehicle prepared just prior to use and administered parenterally. 